Physiologically based pharmacokinetic modeling to assess metabolic drug-drug interaction risks and inform the drug label for fedratinib.

Abstract

PURPOSE:

Fedratinib (INREBIC®), a Janus kinase 2 inhibitor, is approved in the United States to treat patients with myelofibrosis. Fedratinib is not only a substrate of cytochrome P450 (CYP) enzymes, but also exhibits complex auto-inhibition, time-dependent inhibition, or mixed inhibition/induction of CYP enzymes including CYP3A. Therefore, a mechanistic modeling approach was used to characterize pharmacokinetic (PK) properties and assess drug-drug interaction (DDI) potentials for fedratinib under clinical scenarios.

METHODS:

The physiologically based pharmacokinetic (PBPK) model of fedratinib was constructed in Simcyp® (V17R1) by integrating available in vitro and in vivo information and was further parameterized and validated by using clinical PK data.

RESULTS:

The validated PBPK model was applied to predict DDIs between fedratinib and CYP modulators or substrates. The model simulations indicated that the fedratinib-as-victim DDI extent in terms of geometric mean area under curve (AUC) at steady state is about twofold or 1.2-fold when strong or moderate CYP3A4 inhibitors, respectively, are co-administered with repeated doses of fedratinib. In addition, the PBPK model successfully captured the perpetrator DDI effect of fedratinib on a sensitive CY3A4 substrate midazolam and predicted minor effects of fedratinib on CYP2C8/9 substrates.

CONCLUSIONS:

The PBPK-DDI model of fedratinib facilitated drug development by identifying DDI potential, optimizing clinical study designs, supporting waivers for clinical studies, and informing drug label claims. Fedratinib dose should be reduced to 200 mg QD when a strong CYP3A4 inhibitor is co-administered and then re-escalated to 400 mg in a stepwise manner as tolerated after the strong CYP3A4 inhibitor is discontinued.

• Authors: Fan Wu, Gopal Krishna, Sekhar Surapaneni
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 86 Issue 4 Pg. 461-473 (10 2020) ISSN: 1432-0843 [Electronic] Germany
• PMID: 32886148 (Publication Type: Journal Article)

Chemical References

• Cytochrome P-450 CYP3A Inhibitors
• Protein Kinase Inhibitors
• Pyrrolidines
• Sulfonamides
• fedratinib
• CYP2C9 protein, human
• Cytochrome P-450 CYP2C9
• CYP2C8 protein, human
• Cytochrome P-450 CYP2C8
• Cytochrome P-450 CYP3A
• CYP3A4 protein, human
• JAK2 protein, human
• Janus Kinase 2
• Midazolam
• Ketoconazole

Topics

• Area Under Curve
• Computer Simulation
• Cytochrome P-450 CYP2C8 (metabolism)
• Cytochrome P-450 CYP2C9 (metabolism)
• Cytochrome P-450 CYP3A (metabolism)
• Cytochrome P-450 CYP3A Inhibitors (administration & dosage, pharmacokinetics)
• Drug Interactions
• Drug Labeling
• Healthy Volunteers
• Humans
• Janus Kinase 2 (antagonists & inhibitors)
• Ketoconazole (administration & dosage, pharmacokinetics)
• Midazolam (administration & dosage, pharmacokinetics)
• Models, Biological
• Primary Myelofibrosis (drug therapy)
• Protein Kinase Inhibitors (administration & dosage, pharmacokinetics)
• Pyrrolidines (administration & dosage, pharmacokinetics)
• Sulfonamides (administration & dosage, pharmacokinetics)